Highly functionalized heterocycles of various ring sizes, with different heteroatoms and substitution patterns are of major interest in the pharmaceutical and agricultural industry due to the many intrinsic biological properties of these substances.
In medicinal chemistry in general, and combinatorial chemistry in particular, the use of versatile synthons or versatile scaffolds, which are available after only a few reaction steps, are of great interest. An example of a reagent producing such synthons is N,N-dimethylformamide diethyl acetal (DMFDEA), cf. Abdulla, R. F.; Brinkmeyer, R. V., Tetrahedron, 1979, 35, 1675–1735. Condensation reactions between an activated methyl or methylene group adjacent to an ester or keto functionality and DMFDEA form dimethylaminopropenoates(A) or dimethylaminopropenones (B), see FIG. 1.
These intermediates, in which the dimethylamino moiety acts as a good leaving group, have been used in reactions in solution under conventional heating methods which has been described for example in Stanovnik, B.; Svete, J., Synlett, 2000, 8, 1077–1091. The intermediates could then be reacted with dinucleophiles to form different heterocycles. The availability of starting materials, which could form activated alkylaminopropenones or alkylaminopropenoates with DMFDEA is large and the number of possible heterocycles with large diversity, which are possible to form in a subsequential step from these types of intermediates is substantial. The formation of heterocycles from these intermediates takes place via a cascade or domino-type reaction, cf. Tietze, L. F., Chem. Rev., 1996, 115–136, which means that it involves two or more new bond formations taking place under the same reaction conditions. The advantages of this kind of reaction as compared to traditional multi-step reactions are simplified engineering, no intermediate work-up, minimized waste handling and lower cost of purification. All of these are important factors to consider when working the synthesis of combinatorial libraries.
Microwave heating has been used in organic synthesis since 1986, cf. Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J., Tetrahedron Lett. 1986, 27, 279–282. Microwave heating reduces the reaction times in comparison with traditional heating. In addition, the yields of the reactions are often increased and the time for optimizing the reaction conditions is minimized in comparison to conventional heating methods.